Calcitonin-secreting cells of the thyroid express an extracellular calcium receptor gene.

Abstract

Calcitonin (CT) secretion by parafollicular cells of the thyroid (C cells) is regulated by small changes in the concentration of extracellular calcium ([Ca2+]e). Elevation of [Ca2+]e elicits a rise in the C cell cytoplasmic calcium concentration and stimulates CT release. The molecular entity through which C cells detect changes in [Ca2+]e and modulate hormone secretion is unknown. Recently, an extracellular calcium-sensing receptor (CaR) complementary DNA was isolated from bovine parathyroid gland. To assess whether parathyroid cells and C cells use similar mechanisms to detect changes in ambient Ca2+, rat, human, and sheep C cells were examined for expression of the parathyroid CaR or a related receptor isoform. Reverse transcription-polymerase chain reaction analysis identified CaR transcripts in rat and human thyroid gland. Northern blot analysis demonstrated CaR messenger RNA (mRNA) in rat thyroid gland, a human medullary thyroid carcinoma (MTC) isolate, and a highly enriched preparation of sheep C cells. Rat MTC 44-2 cells, a cell line responsive to changes in [Ca2+]e, express abundant levels of CaR mRNA. Human TT cells, a C cell line lacking the extracellular calcium-sensing function, have undetectable levels of CaR mRNA by Northern blot analysis. Western blot analysis, using antiserum specific to the parathyroid CaR, detected CaR protein in rMTC 44-2, but not TT cells. Immunostaining of both dispersed sheep C cells and rat thyroid gland sections identified C cell-specific expression of the CaR protein, and in situ hybridization analysis confirmed the C cell-specific expression of CaR mRNA in the intact rat thyroid. The nucleotide sequence of the coding region of the rMTC 44-2 CaR transcripts was found to encode the same CaR protein as that expressed in the parathyroid and kidney. The results demonstrate that C cells express the same extracellular calcium-sensing receptor that is found in parathyroid and kidney, and the presence of this receptor protein in C cell lines correlates with the extracellular calcium-sensing function. This CaR is likely to represent the primary molecular entity through which C cells detect changes in [Ca2+]e and control CT release, suggesting that activation of the same receptor can either stimulate or inhibit hormone secretion in different cell types.

Calcium Sensing Receptor Activators: Calcimimetics

“…Reports also suggest that calcimimetics lower calcium by a PTH-independent mechanism. Calcimimetics act on the CaR expressed on the thyroid parafollicular C-cells [16] to release calcitonin [17,44] which may lower serum calcium. In addition, the CaR is expressed on the gastric antral G-cells [88] which secrete gastrin and may also play a role in reducing serum calcium levels [56,89].…”

“…In addition, PTH stimulates the synthesis of 1 ,25-dihydroxycholecalciferol (1,25(OH) 2 D 3 or calcitriol) which increases calcium absorption in the small intestine [15]. Besides PTH, the CaR controls the release of calcitonin from the parafollicular C-cells located in the thyroid gland [16]. In this case, increasing levels of extracellular Ca 2+ cause the CaR to stimulate the secretion of calcitonin, a hormone that functions in an opposite manner to PTH.…”

The Calcium Receptor in Health and Disease

“…A high degree of homology is observed between the CaR G from different species. However, a variable number of protein kinase C (PKC) sites are present in the first and the third loop and intracytoplasmic C terminus: 4 in bovine CaR G [8]; 5 in human CaR G [9]; 6 in rabbit CaR G [30], and 7 in rat CaR G [11, 12]. Human [9], rabbit [30], and rat [11], but not bovine [8] CaR G have putative protein kinase A (PKA) phosphorylation sites.…”

“…These two bands may correspond to mono and dimeric forms of the glycosylated CaR G polypeptide of ∼120 kD [8, 9]. …”

“…This receptor is a member of the superfamily of G-protein-coupled receptors. Moreover, it is present not only in classic Ca 2+ -sensing cells, like parathyroid cells and calcitonin-secreting C cells of the thyroid gland [9], but also in the kidney [10, 11], brain [12], bovine pituitary cells [13], keratinocyte [2] and gastrointestinal tract [14]. The physiological role of this G-protein-coupled CaR (CaR G ) has been further supported by the identification of mutations responsible for several hypo- and hypercalcemic hereditary diseases and by the use of genetic knockout in mice [15].…”